DESCRIPTION (Applicant's Abstract): Drug use and drug addiction are among the largest and most challenging problems facing society today. Those individuals who are predisposed or vulnerable to the addictive properties of drugs often engage in this behavior to the point of functional disability and even death through overdose. The cost of drug abuse to the individual, to families, and to society is enormous. Despite the progress that has been made in our understanding of the causes of drug addiction, a more complete understanding of this complex problem will not begin to emerge until a full picture of the molecular and neuronal substrates of addiction is illuminated. This aim is now closer to fulfillment with the advent of DNA microarray-based analysis of gene expression. The goal of the present application is to search for cocaine-responsive genes through the application of microarray analysis to human postmortem brain tissue. Microarrays designed to detect changes in the relative expression of transcription factors/G-protein signaling genes, and of genes important for neuronal structure and function, will be used to identify candidate genes in the nucleus accumbens of chronic cocaine addicts (Specific Aim 1). Together, the low-density microarrays designed for use in this proposal contain all genes whose expression is currently known to be altered by cocaine, plus approximately 2000 genes whose response to cocaine is not known. Transcripts whose relative level of expression is induced or repressed more than 2-fold as determined by data mining of arrays will be selected for independent verification with quantitative polymerase chain reaction assays and in situ hybridization (Specific Aim 2). High density arrays containing more than 30,000 genes are under construction in our institution's Human Genome Facility and these will be employed to extend the search for cocaine-responsive genes in the brains of human cocaine addicts to the genomic level. Microarray-based scanning of the human genome has the potential to establish those genes or gene clusters that define the addictive phenotype, leading the way to proteomic-based studies of the bases of addiction.